Charge density and electrostatic potential of hepatitis C anti-viral agent andrographolide: an experimental and theoretical study

Manjula, S.; Kalaiarasi, C.; Pavan, M.S.; Hathwar, V.R.; Kumaradhas, P.

doi:10.1107/S2052520618014981

Charge density and electrostatic potential of hepatitis C anti-viral agent andrographolide: an experimental and theoretical study

S. Manjula, C. Kalaiarasi, M. S. Pavan, V. R. Hathwar and P. Kumaradhas

Andrographolide (AGH) is a hepatitis C anti-viral agent which targets the host cell by covalently binding with the NF-κBreceptor. The experimental electron density distribution study of AGH has been carried out from high-resolution X-ray diffraction data collected at 110.2 (3) K. The unit-cell packing of AGH was stabilized by strong O—H

O and weak C—H

O types of intermolecular interactions. The dissociation energy of the strong hydrogen bond O2—H22

O1 is very high, 32 kJ mol⁻¹. The percentage occupancy of H

H interactions is found to be maximum (68.5%) when it comparing with the other types of interactions occurring in the AGH crystalline phase. The atomic valance index (V_topo) of the C16 atom is low compared with other carbon atoms; this shows that C16 could be the possible reactive location of the AGH molecule. All atoms in the OH groups have very low V_topo values; this indicates their role in strong hydrogen bonding interactions. The electrostatic potential (ESP) surface of AGH shows the polarization of the C16=C17 bond and ESP contour map shows several maxima at the vicinity of the C16 atom; these results strongly demonstrate that the C16 atom is the reactive location of the AGH molecule. The molecular covalent docking analysis of AGH with the NF-κB receptor has been performed and confirmed this result. The highly electronegative region around γ-butyrolactone can be helpful for initial alignment of the AGH molecule in NF-κB receptor active site. The atomic volumes of the hydrogen atoms which participate in the H

H interaction are found to be low.

Keywords: andrographolide; electron density; hydrogen bonding; electrostatic potential; intermolecular interactions.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2052520618014981/px5005sup1.cif Contains datablock I
	Structure factor file (CIF format) https://doi.org/10.1107/S2052520618014981/px5005Isup2.hkl Contains datablock I
	Portable Document Format (PDF) file https://doi.org/10.1107/S2052520618014981/px5005sup3.pdf Supplementary material

CCDC reference: 1554720

Computing details top

Data collection: 'CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01)' _computing_cell_refinement 'CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01)'; data reduction: 'CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01)'; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: XD2006 (Volkov et al., 2006); molecular graphics: XD2006 (Volkov et al., 2006); software used to prepare material for publication: XD2006 (Volkov et al., 2006).

(I) top

Crystal data top

C₂₀H₃₀O₅	F(000) = 380
M_r = 350.44	D_x = 1.264 Mg m⁻³
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 48814 reflections
a = 6.5162 (1) Å	θ = 3.1–51.3°
b = 7.9477 (1) Å	µ = 0.09 mm⁻¹
c = 17.9185 (2) Å	T = 110 K
β = 97.023 (1)°	Plate, colorless
V = 921.02 (2) Å³	0.43 × 0.28 × 0.23 mm
Z = 2

Data collection top

Xcalibur, Eos, Nova diffractometer	19407 independent reflections
Radiation source: fine-focus sealed tube	16923 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.052
ω scans	θ_max = 50.1°, θ_min = 2.8°
Absorption correction: analytical 'CrysAlisPro, Agilent Technologies,' Version 1.171.38.41 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01) Analytical numeric absorption correction using a multifaceted crystal model based on expressions derived by R.C. Clark & J.S. Reid. (Clark, R. C. & Reid, J. S. (1995). Acta Cryst. A51, 887-897) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.'	h = −14→14
T_min = 0.954, T_max = 0.982	k = −17→17
113191 measured reflections	l = −39→39

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	H-atom parameters not defined?
R[F² > 2σ(F²)] = 0.034	w2 = 1/[s²(F_o²)]
wR(F²) = 0.068	(Δ/σ)_max = 0.001
S = 1.53	Δρ_max = 0.27 e Å⁻³
15841 reflections	Δρ_min = −0.20 e Å⁻³
255 parameters

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.62097 (7)	0.4697 (3)	0.06923 (2)	0.030
O2	0.38461 (5)	0.7408 (3)	0.042046 (19)	0.023
O3	1.62202 (5)	0.9712 (3)	0.586364 (17)	0.019
O4	1.15551 (5)	1.0790 (3)	0.55011 (2)	0.021
O5	1.75414 (5)	1.0221 (3)	0.479101 (19)	0.020
C1	0.75329 (6)	0.7592 (3)	0.096526 (18)	0.015
C2	0.91218 (5)	0.8561 (3)	0.153886 (18)	0.013
C3	0.90739 (5)	0.8166 (3)	0.239090 (17)	0.011
C4	0.91911 (7)	0.6243 (3)	0.24956 (2)	0.018
C5	0.75326 (8)	0.5308 (3)	0.19784 (2)	0.023
C6	0.77060 (7)	0.5689 (3)	0.11589 (2)	0.020
C7	0.52972 (6)	0.8226 (3)	0.09725 (2)	0.019
C8	0.81527 (7)	0.7821 (3)	0.01690 (2)	0.024
C9	0.91635 (8)	1.0466 (3)	0.13947 (2)	0.023
C10	1.10244 (9)	1.1289 (3)	0.18664 (3)	0.025
C11	1.10498 (7)	1.0853 (3)	0.26856 (2)	0.018
C12	1.10533 (5)	0.8983 (3)	0.283162 (17)	0.012
C13	0.71747 (6)	0.8838 (3)	0.27238 (2)	0.020
C14	1.09684 (9)	1.2023 (3)	0.32186 (3)	0.028
C15	1.13990 (5)	0.8520 (3)	0.367064 (18)	0.014
C16	1.34581 (5)	0.9090 (3)	0.404611 (19)	0.014
C17	1.39547 (5)	0.9356 (3)	0.478397 (18)	0.012
C18	1.60732 (5)	0.9801 (3)	0.51101 (2)	0.014
C19	1.43074 (7)	0.9041 (3)	0.60924 (2)	0.022
C20	1.26425 (6)	0.9259 (3)	0.541897 (19)	0.015
H1	0.506745	0.54078	0.049305	0.037
H2	1.06341	0.80798	0.142496	0.031
H4A	0.907999	0.59959	0.308944	0.034
H4B	1.068251	0.585013	0.233617	0.038
H5A	0.597765	0.563233	0.209955	0.042
H5B	0.759907	0.396067	0.209683	0.037
H6	0.924678	0.526505	0.104709	0.038
H7A	0.466281	0.804292	0.150274	0.043
H7B	0.531281	0.959022	0.08923	0.041
H8A	0.726735	0.704466	−0.022849	0.047
H8B	0.975422	0.759705	0.016182	0.053
H8C	0.801519	0.907737	−0.002926	0.042
H9A	0.769426	1.09645	0.153388	0.040
H9B	0.918469	1.073017	0.079763	0.040
H10A	1.09724	1.265703	0.181008	0.044
H10B	1.244737	1.076023	0.16978	0.045
H12	1.230094	0.842795	0.255073	0.027
H13A	0.581643	0.813019	0.256362	0.048
H13B	0.680988	1.009121	0.255112	0.048
H13C	0.749813	0.880967	0.331692	0.046
H14A	1.088869	1.182446	0.380852	0.039
H14B	1.088518	1.333576	0.307059	0.045
H15A	1.022687	0.895735	0.401202	0.032
H15B	1.140514	0.714704	0.370307	0.027
H16	1.470135	0.913437	0.370148	0.031
H19A	1.388335	0.974377	0.657388	0.042
H19B	1.460947	0.77259	0.624937	0.041
H20	1.158696	0.817758	0.540769	0.035
H21	1.019708	1.065311	0.522365	0.036
H22	0.371126	0.812604	−0.001829	0.036

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.03428 (19)	0.02658 (16)	0.02544 (15)	0.00135 (15)	−0.01653 (14)	−0.00946 (13)
O2	0.01551 (11)	0.03119 (16)	0.01907 (12)	−0.00134 (11)	−0.00703 (9)	0.00395 (11)
O3	0.01637 (11)	0.02331 (13)	0.01411 (10)	0.00112 (10)	−0.00601 (8)	−0.00145 (9)
O4	0.01441 (11)	0.02469 (14)	0.02288 (13)	0.00438 (10)	−0.00103 (9)	−0.00966 (11)
O5	0.01147 (10)	0.02380 (14)	0.02270 (13)	−0.00197 (9)	−0.00144 (9)	−0.00060 (11)
C1	0.01249 (12)	0.02372 (16)	0.00874 (10)	0.00286 (11)	−0.00181 (9)	−0.00120 (10)
C2	0.01165 (11)	0.01917 (13)	0.00866 (10)	0.00115 (10)	−0.00007 (8)	0.00122 (9)
C3	0.00988 (10)	0.01542 (12)	0.00817 (9)	−0.00009 (9)	−0.00013 (8)	−0.00053 (9)
C4	0.02110 (16)	0.01594 (13)	0.01342 (12)	−0.00359 (11)	−0.00636 (11)	0.00162 (10)
C5	0.02713 (19)	0.01935 (15)	0.01815 (15)	−0.00685 (14)	−0.00882 (13)	0.00060 (12)
C6	0.02134 (16)	0.02183 (16)	0.01562 (13)	0.00297 (13)	−0.00768 (12)	−0.00533 (12)
C7	0.01277 (12)	0.02974 (19)	0.01273 (12)	0.00438 (12)	−0.00232 (10)	−0.00008 (12)
C8	0.01868 (16)	0.0442 (3)	0.00894 (11)	0.00375 (16)	−0.00007 (10)	−0.00140 (14)
C9	0.02637 (19)	0.02185 (17)	0.01770 (14)	−0.00333 (14)	−0.00609 (13)	0.00771 (13)
C10	0.0279 (2)	0.02365 (18)	0.02265 (17)	−0.00918 (16)	−0.00444 (15)	0.00971 (15)
C11	0.01902 (14)	0.01441 (13)	0.01855 (14)	−0.00271 (11)	−0.00502 (11)	0.00157 (11)
C12	0.01007 (10)	0.01462 (12)	0.00949 (9)	−0.00024 (9)	−0.00037 (8)	0.00007 (9)
C13	0.01087 (12)	0.0357 (2)	0.01444 (12)	0.00149 (13)	0.00138 (10)	−0.00690 (13)
C14	0.0348 (2)	0.01510 (15)	0.0288 (2)	0.00187 (15)	−0.01295 (18)	−0.00410 (14)
C15	0.01171 (11)	0.01966 (14)	0.00937 (10)	−0.00203 (10)	−0.00095 (8)	−0.00060 (9)
C16	0.01053 (11)	0.02037 (14)	0.01038 (10)	−0.00063 (10)	−0.00057 (8)	−0.00215 (10)
C17	0.01051 (11)	0.01601 (12)	0.01026 (10)	0.00054 (9)	−0.00144 (8)	−0.00188 (9)
C18	0.01103 (11)	0.01612 (12)	0.01470 (12)	0.00068 (10)	−0.00351 (9)	−0.00152 (10)
C19	0.01966 (15)	0.0329 (2)	0.01171 (12)	0.00331 (15)	−0.00172 (11)	0.00171 (13)
C20	0.01336 (12)	0.01910 (14)	0.01171 (11)	0.00028 (10)	−0.00047 (9)	−0.00231 (10)
H1	0.036 (3)	0.037938	0.031906	0.000943	−0.012702	−0.003791
H2	0.0239 (18)	0.042959	0.024794	0.004722	0.003704	−0.000933
H4A	0.045 (2)	0.033717	0.020681	−0.009798	−0.002633	0.00357
H4B	0.044 (2)	0.032753	0.03713	0.006089	−0.000797	−0.007312
H5A	0.041 (3)	0.05052	0.032291	−0.008906	−0.003872	−0.000056
H5B	0.041 (3)	0.025801	0.039176	−0.008683	−0.017513	0.002455
H6	0.039 (2)	0.041947	0.031583	0.011764	−0.005939	−0.00971
H7A	0.041 (3)	0.063346	0.024041	−0.00895	0.004575	−0.002998
H7B	0.046 (3)	0.033221	0.040528	0.003003	−0.011436	0.002162
H8A	0.047 (3)	0.066511	0.024862	−0.008165	−0.003613	−0.011166
H8B	0.040 (2)	0.088197	0.029493	0.009261	0.002724	0.000232
H8C	0.044 (3)	0.051412	0.031041	0.001998	0.006001	0.010057
H9A	0.043 (3)	0.034954	0.041101	0.004391	−0.002587	0.000495
H9B	0.046 (3)	0.049161	0.022336	−0.010495	−0.003681	0.011898
H10A	0.053 (3)	0.032155	0.041403	−0.012775	−0.014012	0.01483
H10B	0.042 (2)	0.06066	0.030858	−0.007366	0.001229	0.007901
H12	0.0235 (18)	0.034612	0.023605	0.004005	0.005693	−0.001971
H13A	0.043 (3)	0.056539	0.042862	−0.010848	0.002448	−0.013045
H13B	0.063 (4)	0.036556	0.044678	0.012038	0.007259	0.00392
H13C	0.055 (3)	0.065048	0.018415	0.00593	0.000263	−0.00271
H14A	0.047 (3)	0.03841	0.028059	0.004601	−0.006228	−0.00104
H14B	0.054 (3)	0.020679	0.053591	0.000795	−0.017341	0.006636
H15A	0.032 (2)	0.041149	0.023547	0.00313	0.005656	−0.004656
H15B	0.031 (2)	0.019396	0.029532	−0.001527	−0.004132	0.001198
H16	0.027 (2)	0.04299	0.024926	−0.002	0.006203	−0.002547
H19A	0.046 (3)	0.056019	0.024349	0.000658	0.001705	−0.013764
H19B	0.051 (3)	0.033438	0.034216	−0.003401	−0.005926	0.005147
H20	0.036 (2)	0.044209	0.025818	−0.014326	0.002363	−0.00119
H21	0.024 (2)	0.053682	0.029362	0.007351	−0.004264	−0.014171
H22	0.030 (2)	0.049454	0.026066	0.003983	−0.005713	0.005198

Geometric parameters (Å, º) top

O1—H1	0.9673 (13)	C10—C11	1.5065 (6)
O2—H22	0.9667 (13)	C10—H10A	1.092 (2)
O3—C18	1.3438 (5)	C10—H10B	1.0938 (10)
O4—C20	1.4245 (5)	C11—C12	1.5092 (5)
O4—H21	0.9667 (4)	C11—C14	1.3389 (7)
O5—C18	1.2194 (5)	C12—C15	1.5374 (4)
C2—C9	1.5360 (6)	C12—H12	1.0994 (9)
C2—H2	1.0993 (8)	C13—H13A	1.0583 (12)
C3—C13	1.5341 (5)	C13—H13B	1.061 (2)
C4—C5	1.5280 (5)	C13—H13C	1.0582 (4)
C4—H4A	1.0932 (6)	C14—H14A	1.0763 (7)
C4—H4B	1.0915 (8)	C14—H14B	1.076 (2)
C5—C6	1.5170 (6)	C15—C16	1.4960 (5)
C5—H5A	1.0928 (8)	C15—H15A	1.0922 (8)
C5—H5B	1.091 (2)	C15—H15B	1.092 (2)
C6—H6	1.1005 (8)	C16—C17	1.3390 (4)
C7—H7A	1.0912 (5)	C16—H16	1.0776 (4)
C7—H7B	1.094 (2)	C17—C18	1.4747 (4)
C8—H8A	1.0585 (14)	C17—C20	1.5065 (5)
C8—H8B	1.0603 (6)	C19—C20	1.5307 (5)
C8—H8C	1.060 (2)	C19—H19A	1.0913 (12)
C9—C10	1.5372 (6)	C19—H19B	1.094 (2)
C9—H9A	1.0929 (10)	C20—H20	1.0997 (17)
C9—H9B	1.0921 (6)

C20—O4—H21	106.64 (12)	C3—C13—H13A	113.39 (8)
C9—C2—H2	106.09 (11)	C3—C13—H13B	112.09 (4)
C5—C4—H4A	112.14 (8)	C3—C13—H13C	108.18 (5)
C5—C4—H4B	106.76 (8)	H13A—C13—H13B	105.65 (7)
H4A—C4—H4B	111.74 (8)	H13A—C13—H13C	108.56 (10)
C4—C5—C6	111.03 (4)	H13B—C13—H13C	108.83 (15)
C4—C5—H5A	111.64 (8)	C11—C14—H14A	127.54 (12)
C4—C5—H5B	110.56 (4)	C11—C14—H14B	120.19 (6)
C6—C5—H5A	109.00 (5)	H14A—C14—H14B	112.18 (15)
C6—C5—H5B	112.25 (4)	C12—C15—C16	112.54 (3)
H5A—C5—H5B	102.05 (11)	C12—C15—H15A	116.27 (6)
C5—C6—H6	107.01 (5)	C12—C15—H15B	106.87 (3)
H7A—C7—H7B	104.92 (13)	C16—C15—H15A	107.56 (6)
H8A—C8—H8B	110.50 (13)	C16—C15—H15B	106.36 (3)
H8A—C8—H8C	107.87 (7)	H15A—C15—H15B	106.65 (11)
H8B—C8—H8C	101.37 (12)	C15—C16—C17	125.95 (3)
C2—C9—C10	110.87 (3)	C15—C16—H16	116.61 (5)
C2—C9—H9A	106.57 (11)	C17—C16—H16	116.93 (4)
C2—C9—H9B	110.92 (12)	C16—C17—C18	122.04 (3)
C10—C9—H9A	111.97 (8)	C16—C17—C20	130.30 (3)
C10—C9—H9B	110.67 (7)	C18—C17—C20	107.65 (3)
H9A—C9—H9B	105.67 (9)	O3—C18—O5	121.46 (3)
C9—C10—C11	110.59 (4)	O3—C18—C17	109.49 (3)
C9—C10—H10A	111.09 (4)	O5—C18—C17	129.04 (3)
C9—C10—H10B	108.82 (8)	C20—C19—H19A	109.98 (5)
C11—C10—H10A	108.42 (5)	C20—C19—H19B	113.51 (5)
C11—C10—H10B	105.78 (5)	H19A—C19—H19B	109.92 (8)
H10A—C10—H10B	112.03 (11)	O4—C20—C17	111.71 (3)
C10—C11—C12	113.29 (4)	O4—C20—C19	109.20 (3)
C10—C11—C14	122.57 (4)	O4—C20—H20	110.59 (8)
C12—C11—C14	124.06 (4)	C17—C20—C19	100.85 (3)
C11—C12—C15	113.71 (3)	C17—C20—H20	115.95 (5)
C11—C12—H12	107.52 (11)	C19—C20—H20	107.89 (5)
C15—C12—H12	108.88 (5)

H21—O4—C20—C17	95.14 (14)	C14—C11—C12—H12	−132.38 (17)
H21—O4—C20—C19	−154.18 (15)	C12—C11—C14—H14A	−0.31 (12)
H21—O4—C20—H20	−35.59 (11)	C12—C11—C14—H14B	−176.6 (2)
H2—C2—C9—C10	−55.14 (11)	C11—C12—C15—C16	−62.33 (12)
H2—C2—C9—H9A	−177.23 (14)	C11—C12—C15—H15A	62.35 (13)
H2—C2—C9—H9B	68.23 (12)	C11—C12—C15—H15B	−178.73 (15)
H4A—C4—C5—C6	179.31 (16)	H12—C12—C15—C16	57.52 (12)
H4A—C4—C5—H5A	57.45 (12)	H12—C12—C15—H15A	−177.79 (16)
H4A—C4—C5—H5B	−55.42 (12)	H12—C12—C15—H15B	−58.88 (11)
H4B—C4—C5—C6	−58.00 (12)	C12—C15—C16—C17	157.67 (18)
H4B—C4—C5—H5A	−179.86 (15)	C12—C15—C16—H16	−30.80 (11)
H4B—C4—C5—H5B	67.27 (12)	H15A—C15—C16—C17	28.33 (13)
C4—C5—C6—H6	60.55 (12)	H15A—C15—C16—H16	−160.14 (16)
H5A—C5—C6—H6	−176.06 (15)	H15B—C15—C16—C17	−85.63 (15)
H5B—C5—C6—H6	−63.76 (12)	H15B—C15—C16—H16	85.90 (13)
C2—C9—C10—C11	−53.71 (12)	C15—C16—C17—C18	175.5 (2)
C2—C9—C10—H10A	−174.15 (15)	C15—C16—C17—C20	−3.54 (13)
C2—C9—C10—H10B	62.07 (12)	H16—C16—C17—C18	3.97 (11)
H9A—C9—C10—C11	65.16 (12)	H16—C16—C17—C20	−175.0 (2)
H9A—C9—C10—H10A	−55.28 (12)	C16—C17—C18—O3	−169.51 (18)
H9A—C9—C10—H10B	−179.06 (16)	C16—C17—C18—O5	11.47 (15)
H9B—C9—C10—C11	−177.24 (15)	C16—C17—C20—O4	−84.69 (17)
H9B—C9—C10—H10A	62.33 (12)	C16—C17—C20—C19	159.41 (18)
H9B—C9—C10—H10B	−61.46 (12)	C16—C17—C20—H20	43.24 (14)
C9—C10—C11—C12	56.16 (12)	C20—C17—C18—O3	9.70 (11)
C9—C10—C11—C14	−120.59 (17)	C18—C17—C20—O4	96.19 (13)
H10A—C10—C11—C12	178.17 (15)	C20—C17—C18—O5	−169.3 (2)
H10A—C10—C11—C14	1.42 (12)	C18—C17—C20—C19	−19.71 (10)
H10B—C10—C11—C12	−61.51 (12)	C18—C17—C20—H20	−135.88 (15)
H10B—C10—C11—C14	121.74 (17)	H19A—C19—C20—O4	24.38 (11)
C10—C11—C12—C15	171.54 (16)	H19A—C19—C20—C17	142.12 (13)
C10—C11—C12—H12	50.92 (11)	H19A—C19—C20—H20	−95.87 (13)
C10—C11—C14—H14A	176.1 (2)	H19B—C19—C20—O4	147.99 (15)
C10—C11—C14—H14B	−0.17 (12)	H19B—C19—C20—C17	−94.27 (13)
C14—C11—C12—C15	−11.76 (13)	H19B—C19—C20—H20	27.74 (11)

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